Structured Treatment Interruptions, or STIs, were the subject of a lively session at this year's Conference on Retroviruses and Opportunistic Infections (CROI). Spurred in part by the early closure of enrollment for the SMART study (see below), interest in STIs is higher than in many years. This article reviews the studies presented at CROI and summarizes the state of current understanding on this important subject.

In order to better understand the results of these studies, it is helpful to review the focus of STI research and what previous studies have shown. Interest in STI research is driven by four different and sometimes overlapping goals:

Reinvigorating the immune response,

Helping people with treatment fatigue,

Helping reduce the costs of treatment, and

Helping reduce long-term side effects of treatment.

The following is a brief overview of the rationale for each goal and what research to date has shown.

Reinvigorating the Immune Response

This strategy came from observations that HIV disease progression may be linked to the loss of a type of immune cell, called an HIV-specific cytotoxic lymphocyte (CTL). These cells seek out and destroy HIV-infected cells. Some, but not all, research indicates that some long-term non-progressors -- those who stay well for many years despite HIV and without therapy -- maintain robust levels of potent HIV-specific CTLs while people who progress more rapidly do not.

The goal of one STI approach is to preserve and enhance the body's natural immune responses against HIV infection. In theory, this would help a person's immune system better control HIV on its own for longer, perhaps indefinitely, without therapy. In this context, anti-HIV therapy curbs the destruction of cells by HIV while treatment interruptions are employed to modify the immune response. By starting and stopping therapy periodically, it was hoped that with each successive treatment interruption, the immune system would become more able to recognize and control HIV on its own. This is sometimes called autoimmunization, where it's hoped that enhancing a person's exposure to HIV in a controlled manner can create a more potent and effective response against it.

The results of this research, however, were exactly the opposite of what was hoped. People living with HIV the longest were actually more likely to have more potent CTL response. Those who had started therapy soon after being infected with HIV had a fairly weak CTL response that could be boosted somewhat during an STI, but then decreased again after restarting treatment. Similar results have been found in several other STI studies in people with long-term infection.

Several studies have combined STIs with immune therapies, like IL-2 (Interleukin-2, Proleukin) or therapeutic vaccines. The hope is that they may, when used with an STI, provide the needed lift to orchestrate a stronger immune response to HIV. Although several studies are still ongoing, the results so far have not been promising. As such, people who hope to "boost" their immune response to HIV should not look to STIs as a strategy.

Helping People With Treatment Fatigue

Simply put, treatment fatigue is when a person is "tired" of taking anti-HIV medicines. For people who wish to stop their therapy due to treatment fatigue, the data are conflicting. Results from the various STI studies show that some people can successfully take a break from treatment without developing drug resistance, treatment failure or symptoms of disease progression. For others, such interruptions can be harmful. Several factors have emerged that may help predict when a person may have a worse outcome during their time off treatment. These are:

low CD4+ count (below 200) before starting anti-HIV therapy,

high HIV level (above 55,000) before starting anti-HIV therapy,

poorer control of virus while on therapy or other signs of drug resistance, and

earlier opportunistic infection (OI).

In most studies, at least one-third of volunteers were able to stay off therapy for at least one year. The average time off therapy for the other participants ranged from 8-12 weeks. It should be noted, however, that people who interrupted their treatment had major drops in CD4+ cell counts (on average dropping 50%) compared to people who stayed on treatment. Without proper preventive medicine against OIs, these decreases could be dangerous for people whose counts drop below 200.

A recent and highly publicized study, called SMART, compared several thousand people who used constant therapy to others who stopped treatment whenever their CD4+ cell counts rose above 350. Those who took therapy "breaks" restarted treatment when their CD4+ cell counts fell to 250 or below. Overall, the study showed that people who used continuous treatment were less likely to experience death or disease progression.

Additionally, the study did not show any reduction in drug side effects in the people who cycled on and off therapy as directed by CD4+ cell counts. While this seems to argue against the use of STIs, it is important not to overstate the findings of the SMART trial. What gets lost in the observation that people on continuous therapy did better overall, it is also a fact that a great majority of those taking therapy interruptions fared well too. The actual number of people suffering disease progression or death was quite small in both groups. Perhaps the biggest surprise of the study, though, is that neither CD4+ cell counts nor viral load were able to predict who would experience problems as a result of treatment interruption.

Another unfortunate aspect of the study was that it did not call for patient volunteers to use preventive therapy against the most common opportunistic infections when their CD4+ cell counts fell to levels considered risky. Consequently, the study doesn't tell us anything about the possible role of preventive therapy as part of an STI strategy.

One important observation from SMART is that no matter what its conclusions, it will not stop people from using STIs in many situations. Treatment is still routinely interrupted when a person experiences certain major infections. It is interrupted because of drug side effects. And it will continue to be interrupted by people who suffer serious treatment fatigue. For such people, certain guidelines may be followed. Careful and increased monitoring by your doctor is critical due to the risks for disease progression and OIs. People should check their healthcare benefits (both private insurance or public assistance) to ensure that the cost of additional lab tests would be covered if needed.

Helping Reduce the Costs of Treatment

Interest in using STIs to reduce the cost of treatment has mostly focused on the developing world, where reducing the cost of treatment would increase the number of people who have access to it. Several studies have looked at a kind of STI, called Structured Intermittent Therapy (SIT), where people cycle on and off anti-HIV drugs for specific amounts of time. Most studies to date have shown this strategy to be safe, at least for people who start anti-HIV therapy with CD4 counts above 200.

Helping Reduce the Side Effects of Anti-HIV Therapy

While there is still much to learn about the effects of long-term anti-HIV drug therapy, some consequences are well understood. Two important concerns are lipodystrophy and heart disease.

Lipodystrophy is an umbrella term for three conditions related to how the body regulates and stores fat (lipids). First is the accumulation of fat, usually in the abdomen, the breasts, and around or behind the neck. This is called lipohypertrophy. The second concern is the loss of fat, usually in the arms, legs, buttocks and face. This is called lipoatrophy. The third problem is elevations in two kinds of fats -- called cholesterol and triglycerides -- circulating in the blood. This is called hyperlipidemia.

Studies looking at the connection between anti-HIV drugs and all three kinds of lipodystrophy have yielded somewhat confusing results. While all three problems are more common in people who have taken anti-HIV drugs, they are all sometimes seen in people with HIV who have never taken anti-HIV drugs. To date there are no studies that have shown that STIs affect the risk of lipodystrophy.

A growing set of data show that people with HIV, especially those taking anti-HIV drugs, are at a slightly higher risk of heart disease. A particularly important study on this subject was the DAD study, which found an increased risk of coronary artery disease in people on all types of anti-HIV therapy. Importantly, the DAD study also found that some of the risk was lowered when people stopped taking their anti-HIV drugs.

STIs have been studied to reduce short-term side effects and improve quality of life as well. The studies have shown conflicting results. The first attempt, which had volunteers go on and off therapy every 14 days, resulted in several people developing drug-resistant virus and losing control of their HIV levels. Another small study of continuous cycles of seven days on and seven days off therapy resulted in fewer side effects and better quality of life for people on STIs than for people on continued therapy. HIV levels were well controlled as well. However, a similar study in Thailand had conflicting results, so it's impossible to state for certain whether STIs of this type will be safe.

The SMART trial also weighed in heavily on this issue with surprising and clear findings. Much to the surprise of many, people who interrupted therapy actually had a worse experience with drug side effects, much as they did with the occurrence of opportunistic infections. This is believed to be due to the way the immune system reacts when a person cycles on and off therapy. Whatever the reason, the SMART trial certainly didn't support the use of STIs as a way to reduce drug side effects.

STIs at CROI

Results from several new STI studies were presented at CROI or shortly thereafter. Here we focus on six studies -- SMART, DART, TRIVICAN, PART, WINDOW and ACTG 5170.

SMART

The SMART study was the largest ever STI study, designed to enroll around 6,000 people. It was comparing two anti-HIV drug strategies -- continuous therapy vs. CD4+ cell guided treatment interruptions. One-half of the study participants took anti-HIV drugs throughout the study. The other half started anti-HIV drugs when their CD4+ cell counts fell to 250 and then stopped anti-HIV drugs when their counts rose to 350 (restarting therapy if/when counts again fell below 250).

The SMART study's Data Safety and Monitoring Board (DSMB) -- a group of scientists not connected to the study and researchers charged with protecting the safety of study participants -- halted enrollment due to a higher rate of disease progression, death and other serious health problems in the STI group compared to those on continuous therapy. Further, they advised that volunteers in the STI group switch to continuous therapy due to the safety concerns that emerged from interrupting therapy.

The first public presentation of the data that led to the DSMB's decision was at this year's CROI. The researchers found higher rates of disease progression or death (2.15 times), serious AIDS-related events (5.82 times), and non-HIV related events like heart attack, liver disease (1.6 times) and death (1.6 times) among those interrupting therapy. These results led the DSMB to decide that the STI strategy used was too risky. In addition to closing enrollment, the researchers recommended that everyone who had stopped taking anti-HIV drugs restart them.

It is important to remember, as stated above, that the actual incidence of disease progression and death remained low overall. An increase of 2.15 times might sound impressive, but if it is 2.15 times a low number, then the result is still a low number and a low percentage of people suffering progression. This aspect of the SMART data has been largely overlooked. We point it out here in hopes that people who are using STIs and doing well need not feel overly frightened by the reports from the SMART trial. The trial significantly adds to the data that people can use in making their decisions about STIs. It does not conclude that everyone taking an STI faces imminent danger of death or disease progression as some reports have seemed to imply.

While many expected there would be more disease progression and AIDS-related problems in people on STIs, the higher rates of non-HIV health problems -- especially heart disease -- surprised many. In fact the researchers who designed SMART believed they would see fewer such problems in the STI group.

There are two broad lines of thinking on the SMART findings. Some question the CD4+ parameters used to start and stop therapy in the STI group, arguing that 250 might be too low and 350 might be too close to 250. Others speculated on the role that HIV itself might be playing in heart and kidney disease. These doctors and scientists wondered what role inflammation due to unchecked HIV replication might play in the higher rates of these problems seen in the people on STIs.

DART

In March 2006, researchers from the DART trial, which is studying different anti-HIV drug strategies in Africa, announced a similar decision to stop an STI arm of their study. The STI strategy used in DART was different than the CD4+ guided strategy in SMART. DART used a Structured Intermittent Therapy (SIT) strategy that had people alternating between twelve-week cycles on and off anti-HIV meds. Researchers stopped the SIT part of the study because people in that group had about four times the risk of disease progression or death than those on continuous anti-HIV drug therapy. The trial will continue to study whether health monitoring plus lab tests vs. health monitoring alone is better for people taking anti-HIV drugs in Africa. Given there are many areas of Africa without access to lab tests, it will be important to know if health monitoring alone will result in improved outcomes and the safe use of therapy. If not, anti-HIV drugs might only be available in areas where lab tests are available -- an important question for developing nations.

TRIVICAN

The TRIVICAN study compared three anti-HIV drug strategies: continuous treatment (CT), CD4+ guided treatment (with the same basic criteria used in the SMART trial), and intermittent therapy (with two-month interruptions alternating with four months on therapy). The researchers halted the CD4+ guided arm due to a marked increase in the risk of disease progression and death. The other two arms of the study continue. It's unclear why the SIT arm of this study didn't show the same negative results as was observed in the DART study. Perhaps twelve weeks off therapy is just too long to let HIV remain unchecked, whereas the eight weeks being studied in TRIVICAN is reasonable. Until more research is done on this strategy, with more consistent results, it is wise for people to be cautious.

PART

One last presentation at CROI held mixed news for STIs. The PART trial compared continuous treatment to cycles of intermittent treatment. Those in the intermittent arm would alternate between cycles of three months taking anti-HIV drugs and increasingly long interruptions, starting at one month and increasing to three months by the end of the study. People had an average CD4+ cell count of 700 at the beginning of the study. Researchers reported a high dropout rate in the STI group, due to large drops in CD4+ cell counts. People with lower pre-study CD4+ cell counts, people with lower CD4 nadir (or lowest ever CD4+ cell count), and those living with HIV for a long time were more likely to see major losses in CD4+ cell counts. Importantly, most people in the STI arm who restarted treatment were able to re-suppress HIV replication. There weren't significant differences in HIV drug resistance between the arms.

WINDOW

A couple of other studies drew different conclusions. The WINDOW trial compared continuous therapy vs. six cycles of eight weeks on, eight weeks off intermittent therapy. In contrast to the SMART, DART, TRIVACAN and PART studies, WINDOW researchers found that people in both arms of the trial had low rates of HIV-related illnesses. Researchers did report higher rates of thrush (oral candidiasis) and idiopathic thrombocytopenic purpura (ITP) -- both signs of immune dysfunction -- in the intermittent therapy group, but they considered the differences insignificant.

Perhaps the biggest difference between this trial and others like SMART was how the researchers chose to describe their results. Most trials focused on the rates of increased risk associated with treatment interruption. The reports from WINDOW instead focused on the overall levels of disease progression, rather than the difference between the treatment arms. Both points can be (and are) true of many of these studies.

ACTG 5170

Another study, ACTG 5170, examined what factors might predict the results from a single treatment interruption. The findings reported at CROI were consistent with many earlier studies. The researchers found that when people stopped taking their meds, they saw a rapid increase in viral load and decrease in CD4+ cell count followed by a plateau in both after a few weeks. Importantly, they also found a very low risk of disease progression. The factors in this study that helped predict the results from the single interruption were lowest ever CD4+ cell count (nadir) and starting the study with a detectable viral load.

What Does This All Mean?

How do these studies add to or change our understanding of STIs? There are several conclusions to be reached from these studies. The first is that the hope that STIs would reduce the risk of heart disease and other unintended effects of anti-HIV drug therapy was unsupported by these studies. It is important to caution that each of the studies that found negative results from STIs found them after a relatively short period of time and in an overall context of low net levels of disease progression. The question of the effects of STIs on long-term outcomes remained largely unanswered. However, people considering STIs need to be aware of these short-term risks.

Some of these results, especially those from WINDOW and ACTG 5170, support the idea that while STIs carry some known risks; they can be done safely for some people. A careful analysis of other studies, including SMART, shows the same thing, though it is not emphasized by the study investigators. It appears that STIs are safest for people who have never had very low (under 200) CD4+ cell counts and who were able to reduce viral load to undetectable levels while on anti-HIV therapy, though even this was questionable in the SMART study. None of these studies looked at the question of reinvigorating the immune response, nor have any yet examined the overall cost of therapy.

Taken together, many of these studies show that interrupting therapy carries with it some increased risk of disease progression. People considering an STI may discuss the relative risks with their doctors and develop a strategy for increased monitoring of their health while off anti-HIV treatment. Certainly no one is encouraging treatment interruption when CD4+ cell counts are below 200, whatsoever. Also, there is no support for discontinuation of OI preventive or maintenance therapy when those therapies are indicated. Also, while individuals might have interest, outside of studies, to experiment with STIs, the trade off for interrupting therapy is increased monitoring. Community experience has shown time and again those who wind up in the most troubling and dire health situation are those who stop therapy and don't increase monitoring of their health, CD4+ cell counts and HIV levels.

While the results of some STI studies have not been what many had hoped, a compelling need to continue studies on this subject remains. The prospect of non-stop, life-long anti-HIV therapy is daunting for many. The possibility that this long-term treatment can contribute to a higher risk of heart disease, diabetes and other troubling health consequences also supports the need for more research.

The high hopes for STIs may have indeed faded, but the questions are far from fully settled. Some people with HIV will still want to take time off their HIV meds. This might be to reduce exposure to the drugs and their toxicities, or just due to treatment fatigue. It is vital that doctors and scientists continue to study this important topic, to better understand the safest and most helpful ways for people with HIV to interrupt their treatment.

This article was provided by Project Inform. It is a part of the publication Project Inform Perspective.
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